The E3 ubiquitin ligase Asb2ß is downregulated in a mouse model of hypertrophic cardiomyopathy and targets desmin for proteasomal degradation.
J Mol Cell Cardiol
; 87: 214-24, 2015 Oct.
Article
em En
| MEDLINE
| ID: mdl-26343497
ABSTRACT
BACKGROUND:
Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disease with mutations in genes encoding sarcomeric proteins. Previous findings suggest deregulation of the ubiquitin proteasome system (UPS) in HCM in humans and in a mouse model of HCM (Mybpc3-targeted knock-in (KI) mice). In this study we investigated transcript levels of several muscle-specific E3 ubiquitin ligases in KI mice and aimed at identifying novel protein targets. METHODS ANDRESULTS:
Out of 9 muscle-specific E3 ligases, Asb2ß was found with the lowest mRNA level in KI compared to wild-type (WT) mice. After adenoviral-mediated Asb2ß transduction of WT neonatal mouse cardiomyocytes with either a WT or inactive Asb2ß mutant, desmin was identified as a new target of Asb2ß by mass spectrometry, co-immunoprecipitation and immunoblotting. Immunofluorescence analysis revealed a co-localization of desmin with Asb2ß at the Z-disk of the sarcomere. Knock-down of Asb2ß in cardiomyocytes resulted in higher desmin protein levels. Furthermore, desmin levels were higher in ventricular samples of HCM mice and patients than controls.CONCLUSIONS:
This study identifies desmin as a new Asb2ß target for proteasomal degradation in cardiomyocytes and suggests that accumulation of desmin could contribute to UPS impairment in HCM mice and patients.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cardiomiopatia Hipertrófica
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Miócitos Cardíacos
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Proteínas Adaptadoras de Transdução de Sinal
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Desmina
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Miocárdio
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Mol Cell Cardiol
Ano de publicação:
2015
Tipo de documento:
Article